This program proposes to identify causes of pulmonary edema due primarily to change within the lung circulation, to clarify physiological, biochemical and physical sequences of events involved in these changes, to clarify relationships between pulmonary vascular function and lung mechanics and to develop quantitative methods for measuring lung vascular permeability in humans. In chronically instrumented, unanesthetized sheep where lung lymph can be collected, we will study effects of prostaglandins on the lung circulation and define the roles of prostaglandins and other arachidonate products in pulmonary vascular responses to endotoxemia and oxygen toxicity. We will measure the effects of agents which may prevent endogenous mediator release on the pulmonary vascular response to endotoxemia. We will measure the effects of pulmonary vasoconstriction, pulmonary vascular congestion and pulmonary edema on lung mechanics and investigate mechanisms of those effects. In humans, we will make detailed pulmonary function and hemodynamic measurements in diseases where pulmonary edema occurs without heart failure, follow the course of those changes and evaluate indicator dilution methods for measuring lung vascular permeability. Using data from animal and human experiments, we will develop mathematical models of lung transvascular transport which describe the physical events involved in this process under normal and abnormal conditions and permits accurate and precise measurements of lung vascular permeability in humans.